Author Topic: A great CTH method  (Read 17575 times)

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armageddon

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methylimine to methylamph
« Reply #20 on: March 23, 2004, 04:27:00 PM »
Thank you Barium! I have read sunlights (excellent) CTH thread several times, but still I have overread important facts, as you showed me  :o ..

And as the rxn proceeds at room temp. it wouldn't be a great deal to try it with careful addition of some nitromethane (being reduced to methylamine) instead of ammonia, perhaps with external cooling (nitromethane loves being reduced and evolves considerable heat) to see if methylamphetamine would bee the result. Or if it doesn't work this way, one could at least try it with methylamine (from MeNH2*HCl and NaOH) premixed with phenylacetone, should work as far as I understand (tell me if I'm wrong here). Still the advantage would be to avoid nasty, poisonous Al-(whatever)-sludges  :( .

Josef_k: sorry to say, but the procedure is bullshit (sorry dreamer), SWIM tried the procedure several times, also with exact amounts of lab-grade high purity chemicals and bright-yellow, sparkling nitropropene as substrate, and got next to nothing (~1% of theory), so you could as well try it with Zn/HCl and yield up with roughly the same amount - next to NOTHING! >:(  When SWIM reduced first with borohydride, followed by Pd/C-ammoniumformate CTH, yields climbed way up (still not same as, let's say, Bandil, Barium or GC_MS to name a few, but I think that SWIMs skilled enough so he should have got at least SOMEthing IF this procedure would work AT ALL or even only half as good as described by dreamer.

Would just bee too easy, I keep saying! ::)

Greetz A

--oh, laughing is good for your health:

http://195.92.224.73/j20/content/mainhost.asp

 ;D

armageddon

  • Guest
ketone + amine + borohydride - no catalyst at all?
« Reply #21 on: March 24, 2004, 09:44:00 AM »
Well, I just stumbled over following thread:

Post 461926

(cublium: "NaBH4 is just amazing.", Newbee Forum)

Apparently imines are protonated with plain borohydride - so there is no need for any catalyst at all if you have ketone and methylamine?

Just throw ketone and amine together with some solvent, add borohydride under cooling, let stir for a while - et voilà, methylated amphetamine? WAY too easy I think! :o  That means every fool can make meth once he gets his hands on some NaBH4!! (well almost  ;) )

So the "only" use left for SWIMs Pd/C would bee formate CTHs where non-methylated amines are desired. Hm.

Oh, by the way: what about ring-substituted, methylated amphetamines, "psychedelic methamphetamine analogues"? Are they psychoactive at all? Does PIHKAL include some? I don't think so, but I'm just guessing..

Rhodium

  • Guest
Several dozens of methods are available...
« Reply #22 on: March 24, 2004, 12:35:00 PM »
Apparently imines are protonated with plain borohydride - so there is no need for any catalyst at all if you have ketone and methylamine?

Imines aren't protonated by borohydride, they are reduced. NaBH4 is a reducing agent in its own right, so yes, it can also be used for reductive amination (preferably under water-free conditions, but gives moderate yields without).


Barium

  • Guest
Ahem! Someone really need to UTFSE a bit. :-P
« Reply #23 on: March 24, 2004, 05:58:00 PM »
Ahem! Someone really needs to UTFSE a bit.  :P

armageddon

  • Guest
euhmm... yes.
« Reply #24 on: March 25, 2004, 12:11:00 PM »
I'm ashamed, all those things indeed are there, I was just too lazy to UTFSE. I was just searching in the wrong direction.. ;)

armageddon

  • Guest
back to the subject ;^)
« Reply #25 on: March 26, 2004, 08:09:00 AM »
Ok I think this thread got a bit sidetracked because I just wasn't able to shut up (as usual, but where else can you talk to someone about OUR interests?) So I believe its time to post something reasonable.

nitrostyrene->amine with Pd/C/amm formate CTH pseudo-one-pot style, this is how SWIA does it:

100mmol (16,3 gram) nitrostyrene (P2NP, HIGH purity)
150mmol (5,7 gr) borohydride (NaBH4)
115 ml IPA
45 ml H2O
some xx ml 60% acetic acid (didn't measure)
~2 ml GAA
500mmol (~31g) NH4COOH
4,2 grams Pd/C 10% (bought, not homemade)

a) Borohydride reduction First SWIA dissolved 5,7g borohydride in 115ml IPA and 45ml water with good stirring. After it had dissolved he added his nitropropene in small portions so that rxn didn't become too violent (gas/heat evolution made this necessary). The addition took 20 minutes, every portion nitropropene caused a color change to yellow which faded to almost white very quickly. After the addition everything was stirred for another 30 minutes, then ~5ml water was added, followed by small amounts of 60% AcOH (to destroy excess borohydride) until gas evolution had ceased completely and the mixture had become almost colorless, then a last 2ml was added. The rxn mixture was decanted from some white, sticky borate goo at the bottom, saturated with NaCl and the resulting upper alcohol layer (slightly yellowish) was separated and washed again with brine.

b) Pd/C CTH Next, SWIA weighed out 4,2 grams of 10% Pd/C (one half of it was already used and reactivated, and the other half was fresh from the bottle), put them in a 250ml RBF (bit too small ::) ), added the IPA/nitropropane solution gotten from the borohydride reduction and introduced ~31 grams ammonium formate. This was stirred violently for 5 minutes to dissolve as much formate as possible and then a reflux condenser was attached and temp. was slowly raised to 65°C on a water bath. When this temp was reached 45 minutes had passed already, but the rxn had just started to evolve lots of CO2 and apparently hydrogenation had just begun, so SWIA decided to let it run at least another 45 mins. In the end, he waited until gas evolution had nearly ceased (to be sure hydrogenation was complete), took 3 hours in total (from additon of formate until heat was removed and the condenser was disconnected). After 1,5hrs 2ml GAA were added to prevent bicarbonate clogging in the condenser. After rxn had cooled down to RT it was filtered (very nice, clear, bright yellow soln, smelled alot ammonia) and saturated with NaCl. The resulting alcohol layer was separated, aeq. phase extracted once with 50ml toluene and the extraction and alc. layer combined, washed with sat. NaOH and then brine in order to remove ammonia (smelled still like household cleaner :) ). Then, SHOCK! SWIAs only drying agent at hand is CaCl2, not suited for drying amines, nor alcohols. Well, SWIA thought, perhaps the water will bee removed azeotropically when I distill away some solvent (thinking of dean-stark traps), so he cooled, added solid NaCl until soln. became clear, and distilled almost all solvent away and was left with a dark yellow, oily residue with a strong amine smell.. (perhaps vac. dist. would've been better here, before applying heat the color was WAY brighter, obvioulsy something got decomposed; but SWIA has only ONE tap, no pump, hence he can only distill, reflux OR vac.filter, none of these at the same time >:( )
The residue was dissolved in 4x its volume IPA, H2SO4 98% was added in 0,1ml aliquots, everytime the solution got slurried with crystals SWIA added a few ml's Et2O and filtered. The crystals were washed with more Et2O (2x) until they had a shiny white color. Yield: 5,4 grams (phenyl-2-aminopropane)2*H2SO4, 29% of theory (based on starting material phenyl-2-nitropropene) But SWIA suspects yields would've been higher if he had used REALLY anhydrous solvents for crystallization... ::)  And he's very sure that without his attempt to dry a solution by azeotrope distillation, the salt obtained would've been very pure (without washing), as the crude amine soln. had a very pale yellow color (really nice appearance for freebase!)

But more important: it works simple, fast and WITHOUT having to isolate the intermediate nitropropane!
Next time SWIA will try it with KCOOH to see if rxn time can perhaps be shortened..

greetz A


Oh I forgot: in SWIAs opinion there was no need to do an A/B because normally, after ABing/extracting his non-polar has the same color like the post-rxn solution he got this time, so he assumed that there were very few side products (besides they don't really interfer when making the sulfate - opposed to water ;) ). And furthermore the very strong ammonia smell convinced SWIA that the mixtr. was already basic enough to release its goodies upon Xtraction.. with KCOOH that's perhaps not the case - or is it perhaps decomposed to KOH? Then there would bee no need to basify, too, right?
S. Ram & R.E. Ehrenkaufer report the use of a somewhat  similar procedure: "..the catalyst was removed by filtration through a celite pad and washed with dry methanol (10ml). The filtrate was evaporated either under reduced or at normal pressure. The resulting residue was triturated with water (10-25ml), product was extracted with an organic solvent (i.e. ether, DCM or chloroform) and dried over Na2SO4. The organic layer on evaporation gave the desired amino derivative. Some products were directly converted into the HCl-salt with ethereal-HCl without evaporation of ether layer."

(from: A General Procedure for Mild and Rapid Reduction of Alipathic and Aromatic Nitro Compounds Using Ammonium Formate as a Catalytic Hydrogen Transfer Agent, Tetrahedron Letters 25(32), 3415-3418 (1984))

And the idea of azeotropically drying a solution with an apropriate solvent (toluene, benzene etc.) isn't that wierd like SWIA first thought: its in this thread, Barium uses it here

Post 384333

(Barium: "Dare I say quantitative yield", Novel Discourse)
to remove water from post-cth mixture with toluene, but he used a rotovap, seems as if normal distillation does no good to freebase amphetamines in this case... :(
Barium, do you think that not acidifying before removing the solvent/alcohol reduces yield? (->steam distillation?)
Or perhaps basifying everything bee4 the first extraction would be good? SWIA was under the impression that the mixtr. was nearly saturated with ammonia, but I think the yield could be raised quite a bit with some modifications... freebase looked REALLY nice, clean, bright - BEFORE SWIA reduced the volume of its solution... >:(  and I think the procedure could surely be modified to give good purity AND good yields - but how?

To Ganesha: Scrape matchbooks, hm?  :P

armageddon

  • Guest
halogenation?
« Reply #26 on: April 22, 2004, 07:01:00 AM »
Hi!

The FSE is still down ( :o ), so I have to reply to myself because of not being able to find a better thread...
..sorry.

I wonder if one could avoid the use of borohydride if the nitropropene was chlorinated before doing a CTH.
The chlorine ion adds to the beta-carbon, replacing the double bond. As this rxn is reversible, acidic medium would be required (thx for pointing me to that, nicodem  :) ) to prevent the chloro-nitropropane intermediate from being dehalogenated again.
But acidic environment would interfer with the use of ammonium formate as hydrogen donor.
I'm a bit usure whether ammonium ions are useful in this CTH reduction, but the use of ammonium chloride (stable in HCl) would help if this was the case.
Question: how does formic acid behave in dil. HCl solutions? It would give a nice hydrogen donor, while maintaining acidic conditions.
And I don't think it will, but just to be sure: HCl isn't decomposed to hydrogen and chlorine (cough!) by Pd/C, is it?
I know nitropropenes can be reduced by halogenation at the beta-carbon (with HCl(g)) and dehalogenation/reduction with Pd/C and hydrogen under pressure, so I started wondering if it could be possible to use the technique of halogenating nitroalkenes in a CTH reduction...

(operating with vessels under pressure with hydrogen/HCl(g) isn't my thing  ;D )

Any comments, thoughts, critique?

Greetz A


Nicodem

  • Guest
I wonder if one could avoid the use of ...
« Reply #27 on: April 22, 2004, 03:37:00 PM »
I wonder if one could avoid the use of borohydride if the nitropropene was chlorinated before doing a CTH.

If it works with H2 there is a good chance it will work in a CTH reaction as well. Assuming, off course, that you use a hydrogen donor usable in a highly acidic environment (no, ammonium formate won't work - there are other hydrogen donor besides this one). And I assume you are talking about hydrohalogenation and not chlorination as you wrote. This hydrohalogenation or Michael addition of HCl (for some historical reasons also called Antimarkovnikov addition of HCl) is not the same as chlorination (addition of Cl2)!

I'm a bit usure whether ammonium ions are useful in this CTH reduction, but the use of ammonium chloride (stable in HCl) would help if this was the case.

Maybe you could at least explain how you think ammonium ions can be useful in a CTH reduction. What you need is a hydrogen donor, something like the formate anion, hypophosphite anion, hydrazine, cyclohexene, isopropanol or whatever that can donate a hydrogen at the given conditions (acidic in your case).

Question: how does formic acid behave in dil. HCl solutions? It would give a nice hydrogen donor, while maintaining acidic conditions.

It sucks. Formic acid is poorly dissociated compared to the practically fully dissociated ammonium or potassium formate. If you add HCl to formic acid it will shift the dissociation equation even more to the left leaving even less (read as "no") formate anions for the CTH.

I know nitropropenes can be reduced by halogenation at the beta-carbon (with HCl(g)) and dehalogenation/reduction with Pd/C and hydrogen under pressure

Who told you that you need pressure? If plain nitrostyrenes reduce under atmospheric pressure, why should phenylnitropropenes need more pressure? Maybe they do, but I would at least try at normal pressure before claiming that. And if you have the same paper in mind as I do, it is not HCl(g) but conc. HCl(aq). If otherwise please give me the ref because I did not read that yet.


armageddon

  • Guest
changing refs
« Reply #28 on: April 22, 2004, 07:50:00 PM »
Hi Nicodem!

The reason why I stick with my ammonium ions is because

Post 335851

(Sunlight: "MDA and MDMA from CTH reductive amination", Novel Discourse)
reduces ketones with ammonium formate AND ammonium acetate and

Post 477266 (missing)

(Lego: "Reduction of oximes with zinc/ammonium formate", Novel Discourse)
posted an article stating that ammonium chloride can be used (longer rxn time) instead of ammonium formate in the reduction of alipathic nitro compounds. (So I think ammonium ions can be hydrogen donor, too...)
And as there are different theories about the intermediates involved in cth reductions, I thought an ammonia releasing hydrogen donor could be useful when reducing nitro group via cth - perhaps the ammonia helps forming one of the better reducable intermediates? (at least it doesn't interfer with CTH).

The paper I meant only says a few sentences about hydrohalogenation (you're right, oops) and reduction via pd/c-H2. You can find it here:

Patent US6399828

  (for me this link didn't work, here's another one:)

http://l2.espacenet.com/dips/viewer?PN=US6399828&CY=gb&LG=en&DB=EPD



But as I read it I realize it says "Chlorination of norephedrine with thionyl chloride, followed by catalytic hydrogenation of the resulting hydrochloride, gave amphetamine."
Anyway, chlorination of a -OH group or hydrochlorination of a C=C bond - the result is the same, isn't it?

I wonder how they managed to isolate the hydrochloride of phenyl-1-chloro-2-aminopropane?

Damn, THAT would be nice! If the intermediate chloropropane could bee isolated, NO acidic CTH environment would be needed (perhaps slightly acid, GAA should solve that)!

Oh, please tell me: how could I reduce a nitroalkene "without any pressure" but still with hydrogen gas? Or did you mean regular CTH? Every catalytic hydrogenation I know that yields amphetamines (RaneyNi, Pd/C) requires at least 1 atm pressure to work properly..
(maybe thats different with nitrostyrenes, but they need no borohydride reduction of any double bond at all, since they are readily reduced to phenetylamines for example by regular CTH.. I think about hydrochlorination of nitropropenes as a cheap substitute for borohydride)

Greetz A


Nicodem

  • Guest
Mixing up everything you can?
« Reply #29 on: April 23, 2004, 09:11:00 AM »
Your reasoning about why you like the ammonium ions to be present in a CTH reaction makes no sense whatsoever. Again you are comparing two completely different reduction reactions that cannot bee compared. CTH reduction is not the same as a metal dissolving reduction! You don't need acids like NH4+ in a CTH system to get it run. On the contrary, what you need is a CTH reduction system that still works in a HCl acidic system. There is absolutely no reason whatsoever to add additional acids.

So I think ammonium ions can be hydrogen donor, too...

Could you please explain how do you expect NH4+ to bee a hydrogen donor. Are you implying that at the given conditions it decomposes to H2 and N2? Though this is a theoretically possible reaction it is not going to happen. If you have hydrazine in mind, then yes, hydrazine is an excellent hydrogen donor, but hydrazine is not ammonia. Or maybe you simply confused proton donor (which NH4+ is) with hydrogen donor - these are two completely different things.

Anyway, chlorination of a -OH group or hydrochlorination of a C=C bond - the result is the same, isn't it?

No. The methylamino is not the same as a nitro group. The difference is so enormous that I’m not willing to loose time explaining.

I wonder how they managed to isolate the hydrochloride of phenyl-1-chloro-2-aminopropane?

What’s to wander here? As long as the amino group is protected as its hydrochloride the "chloroephedrine" is a perfectly stable compound. It is only in its freebase form that it decomposes to the aziridine derivative. And if the aziridine forms during the CTH it is by no mean a problem because its reduction product is still methamphetamine.

Oh, please tell me: how could I reduce a nitroalkene "without any pressure" but still with hydrogen gas?

I'll not say UTFSE since it is down. I'll say: "use the search engine at the Rhodium site and you will find the paper you need." I can't understand how can you all the time talk about a procedure about which you obviously did not even read the original literature so far. I can't believe that you want to modify a hydrogenation reaction that you did not even read about so far into a CTH reduction. What's wrong with reading? If the libraries scare you, there are still many papers here on The Hive and at Rhodium's home page that you did not check.

Every catalytic hydrogenation I know that yields amphetamines (RaneyNi, Pd/C) requires at least 1 atm pressure to work properly.

1 atm is the normal atmospheric pressure (hence the name atm from atmosphere – 1atm=1,01325bar=760torr=14,6959PSI=101325Pa). Anything less than 1 atm is considered reduced pressure or under pressure and requires a vacuum pump or, since we are talking about H2 partial pressure, mixing of H2 with an inert gas.


armageddon

  • Guest
Hi Nicodem! Nope, I talked just about a CTH...
« Reply #30 on: April 23, 2004, 05:11:00 PM »
Hi Nicodem!

Nope, I talked just about a CTH for dehalogenating/hydrogenating phenyl-1-chloro-2-aminopropane. I didn't mix up CTH and dissolving metal reduxn. Maybe NH4+ doesn't release hydrogen, but can you say for sure that it is of no advantage? Do you know that there isn't any intermediate compound formed with CTH that would profit from ammonium ion presence (like maybe a ketone) and would get reduced faster? I don't know.

I don't wonder if it's possible, I just would like to know how they did isolate the chloroephedrine. The procedure. Writeup. Anyway.

Methylamino is absolutely not nitro, but where is the methylamino in phenyl-1-chloro-2-aminopropane?? Or the nitro group? (OK if you spell it 1-phenyl-1-chloro-2-methylaminoethane then there is a methyl present, but a nitro?)
I wanted to say: the resulting product (said chloropropane) has the same Cl-ion attached at the first carbon seen from the aryl - if you chlorinate an OH-amino-compound or if you hydrochlorinate a "Ar-C=C(CH3-(nitro)" doublebond (at least in this case). BTW I don't see any methylamino group, just a 2-aminopropane chain with extras  :) . Of course, if you think in styrene terms... well.

But I think Pd/C doesn't care whether it has to do additional work reducing NO2 or whether the amino group is already present. In both cases, it has to dehalogenate (almost) the same phenylpropane - at the same carbon. (Just look at page 2 of the ref I gave u, there's a nice picture, you can see that SoCl2 chlorination of norephedrine results in the same compound as does hydrochlorination of P2NP, only difference is the nitro group. The intermediate is a primary amine...)
I wonder if said HCl+P2NP occurs too when doing a SnCl2/HCl reduction to the ketone?

Oh, and I know the catalytic hydrogenation procedures described at rhods archive. (At least the standard ones  :) )

Did you know "under pressure" also means "with pressure" or pressure above 1 atm?

I would like to see you performing a catalytic hydrogenation with something like argon/hydrogen (3:1 maybe?) and 100 mbar "under pressure"??

Peace A


Nicodem

  • Guest
For the last time
« Reply #31 on: April 24, 2004, 06:40:00 AM »
Nope, I talked just about a CTH for dehalogenating/hydrogenating phenyl-1-chloro-2-aminopropane.

Really!?

Post 477266 (missing)

(Lego: "Reduction of oximes with zinc/ammonium formate", Novel Discourse)
is about a metal dissolving reduction! I really don’t understand how can you see any similarity between the reductions with HCOO-/Pd-C and Zn/NH4+. These are two completely different methods with different mechanisms. Maybe this is the problem. You should first understand the underlying mechanisms and than make your claims. Doing the reverse helps just nobody.

Do you know that there isn't any intermediate compound formed with CTH that would profit from ammonium ion presence (like maybe a ketone) and would get reduced faster?

What can any reduction intermediate gain from an inert ammonium cation in an acidic medium? This is almost as absurd as proposing Na+ to aid the reduction.

I just would like to know how they did isolate the chloroephedrine

You also made the same mistake as I did in the last post - it’s norephedrine and not ephedrine. Anyway, they never isolate the “chloronorephedrine”. Like I already explained you, it is not possible to isolate it as it starts decomposing as soon as it is formed. That is why they use its hydrochloride salt which is stable due to the amino group protection. Besides, what would they want to isolate it for anyway? Please, read the patent again!

Methylamino is absolutely not nitro, but where is the methylamino in phenyl-1-chloro-2-aminopropane?

Like I said I thought the patent used ephedrine (= 1-phenyl-2-methylamino-propanol).
Look, you really cannot compare your 1-phenyl-1-chloro-2-nitropropene with this “cloronorephedrine”. The amino group has practically all the properties diametrically opposite to the nitro group. And the decomposition reactions of the two compounds are very different yielding two completely unrelated types of compounds:

Ph-CHCl-CH(NH2)-Me <=> Ph-CH-NH-CH-Me × HCl
Ph-CHCl-CH(NO2)-Me <=> Ph-CH=C(NO2)-Me + HCl

While the aziridine of the first reaction can still be reduced to the amphetamine by CTH the phenylnitropropene can’t be.

Anyway, I give up. I can’t communicate with someone who only read and see only what he what to read and see. You only make me repeat myself which is very frustrating. Everything you wanted to know was explained, now it is up to you to read everything again and try hard to really understand. I can only suggest you to study more, go to the library, do some literature search and take some time for the chemical theory before you do laboratory work.


armageddon

  • Guest
Wow! Great help!
« Reply #32 on: April 24, 2004, 05:34:00 PM »
Hey, I just wanted to know if there are chances that hydrohalogenation of a nitropropene, followed by CTH in acidic media (or hell, any other useful reduction) with an apropriate hydrogen donor being stable in acidic conditions (which are needed to prevent shifting back to the nitropropene) could work. Also I wanted to know which CTH hydrogen donors are stable in dil. HCl.
The reason was to avoid using borohydride to reduce the double bond of alkenes...

Quoting each of my words and criticizing/correcting every statement isn't really helpful - and I don't see why you question every thing I say - it's not all wrong. I just talk about things I read about before.
And since in the patent they perform a pressure hydrogenation anyway, why should they be concerned about protecting or halogenating any amino or hydroxyl group in order to prevent nitropropene formation? Pd/C hydrogenation under pressure also works on nitropropenes directly, not only with halogenalkane*HCl complexes...

(C'mon, show me where you read that they did NOT isolate the HCl salt! Do you think they write everything with a " * HCl" because wanting to say all rxns are carried out in acidic media? I thought it meant forming hydrochloride complex salts... usually a method of purification!)

Quote: "By another procedure, heating norephedrine with thionyl chloride at reflux temperature, followed by catalytic hydrogenation of the resulting 2-amino-1-chloro-1-phenylpropane hydrochloride, gave amphetamine." (and I think they meant hydrogenation with more than 1 atm pressure, not below 1 atm, BTW)

Oh and a last thing: there is also a reduction method using plain sodium and alcohol I think - Na+ as reducing agent being absurd? I don't know if that's true.

(next time, just say "Don't think this will work", instead of telling me I'm such an idiot contrasted to you being SOO clever, ok? That should suffice, too!)


Rhodium

  • Guest
Read up on your chemistry first, THEN post
« Reply #33 on: April 24, 2004, 08:55:00 PM »
Oh and a last thing: there is also a reduction method using plain sodium and alcohol I think - Na+ as reducing agent being absurd? I don't know if that's true.

"Plain sodium" (the metal) is Na, not Na+ - the latter is a sodium ion, which is ridiculously inert. You cannot reduce anything with Na+.

Armageddon: I don't want to see any flamewar in this thread, so quit arguing when you have no hard data to back up your statements with. I'm sorry to have to tell you this, but Nicodem is right in what he is saying above, and you have several inconsistencies and factual errors in each of your posts above.